Nanoscopic biomaterials that are able to mimic structural aspects of biological transport systems such as lipoproteins and viruses are promising targetable transport systems for low molecular weight drugs, recombinant proteins, and genes. Poly(ethylene oxide)-block-poly(L amino acid) (PEO-b-PLAA) self-assembles into micelles, supramolecular core/shell structures, which mimic lipoproteins. As such, they have demonstrated prolonged residence time in blood and low uptake by macrophages. The long-term objective of this research is the development of these diblock copolymer micelles into lipoprotein-like transport systems for hydrophobic drugs. The cores of these micelles may be built from L amino acids or unnatural L amino acids, providing nonpolar domains with varied properties, such as polarity and viscosity. These properties of the core affect drug solubilization, drug release, and micellar break-up. Hence, micelles of PEO-b-PLAA may be tailored for an individual drug, based on knowledge of its properties and drug transport requirements. This concept will be explored for amphotericin B (AmB), the key drug for systemic fungal diseases. The membrane-active drug also has immunomodulatory and antiviral activity. However, due to its poor water solubility and high toxicity, its potential as a drug has not been fully exploited. Recently, it has been shown that the toxicity is due to aggregated species of AmB and that monomeric AmB is non-toxic, but active against fungal cells. If AmB could be anchored onto artificial lipoproteins and transported to target cells or organs in a monomeric state, this would open up new horizons in AmB therapy. The specific aims of this proposal: (1) To prepare micelles of PEO-b-PLAA composed of a homologous series of aliphatic L amino acids or unnatural L amino acids, mimicking the cores of lipoproteins. (2) To characterize these micelles, especially the properties of the cores by fluorescent probe technique. (3) To evaluate the solubilization of AmB by these micelles, assessing solubilized levels, aggregation state, and location in the micelles (spectroscopic study). (4) to evaluate the release of AmB from these micelles in terms of release rate and aggregation state, assessing drug transfer to lipid vesicles or sterols. (5) To evaluate the in vitro antifungal activity and the in vitro/in vivo toxicity of AmB transported by micelles based PEO-b-PLAA, making comparisons with PEO-b-PLAA.